Prominent Lectin-Like Oxidized Low Density Lipoprotein (LDL) Receptor-1 (LOX-1) Expression in Atherosclerotic Lesions Is Associated with Tissue Factor Expression and Apoptosis in Hypercholesterolemic Rabbits

Abstract

Rupture or erosion of vulnerable atherosclerotic plaques and the subsequent formation of occlusive thrombi are currently recognized as the primary causes of acute coronary syndrome and stroke. 1) Vulnerability of atherosclerotic plaques, rather than severity of luminal stenosis, has been suggested to be the most important determinant for the onset of acute coronary syndrome.2) Accordingly, it is of great importance to determine causative factors in the destabilization of atherosclerotic plaques and in the thrombus formation, which should help develop new therapeutic and diagnostic (imaging) agents of atherosclerosis, leading to the establishment of novel therapeutic strategies for preventing acute coronary syndromes and stroke.To date, enhanced proinflammatory responses and the expression of matrix metalloproteinases (MMPs) have been suggested to play important roles in the destabilization of atherosclerotic plaques. Apoptosis and prothrombotic factors in atherosclerotic plaques have also been reported to be crucial factors for the plaque vulnerability and thrombus formation.3) Apoptosis of foam cells and macrophages contributes to the formation of an acellular (cell-poor) lipid core, 4) and the apoptosis of smooth muscle cells further weaken the fibrous cap by decreasing the synthesis of extracellular matrix proteins.5) Tissue factor (TF), a cofactor for plasma coagulation factor VIIa, which is localized in vascular cells and the lipid core within the atherosclerotic lesions, is an initiator of the coagulation cascade leading to thrombus formation after the plaque rupture in vivo. 3)Lectin-like oxidized low density lipoprotein (LDL) receptor-1 (LOX-1), a type II membrane glycoprotein belonging to the C-type lectin family, acts as a cell-surface receptor for oxidized LDL (Ox-LDL) and mediates several biological effects of Ox-LDL.6) Recent studies with cultured cells suggest that LOX-1 may play several important roles in destabilization of atherosclerotic plaques, inducing expression of adhesion molecules and chemokines for monocytes, 7) transformation of macrophages into foam cells, 8,9) apoptosis of smooth muscle cells 10,11) and the degradation of extracellular matrix proteins by induction of matrix metalloproteinases.12) Several studies with cultured cells also showed that Ox-LDL, through LOX-1, also triggers the CD40/CD40L signaling pathway, 13,14) which then induce TF expression. 15) These biological effects mediated by Ox-LDL-LOX-1 interactions may enlarge the lipid core, weaken the fibromuscular cap, and induce proinflammatory responses, resulting in destabilization of the atherosclerotic plaques and thrombus formation.The actual contribution of LOX-1 to the plaque vulnerability and thrombus formation in vivo, however, remains unclear. In this context, we recently demonstrated that LOX-1 expression is related to MMP-9 expression and morphological plaque vulnerability using a rabbit model of spontaneous atherosclerosis, 16) myocardial infarction-prone Watanabe her- Background: Despite increasing in vitro e...

The Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 and its Soluble Form: Cardiovascular Implications

“…In hypercholesterolemic rabbits, LOX-1 expression was more prominent in atherosclerotic plaques with a thinner fibromuscular cap and was localized to the macrophage-rich lipid core 99) . Moreover, in the same areas, LOX-1 expression was positively correlated with tissue factor expression and apoptosis, suggesting the involvement of LOX-1 in the destabilization and rupture of atherosclerotic lesions and the subsequent formation of thrombi 100) . Since LOX-1 could be implicated in vascular cell dysfunction related to plaque instability, it has been investigated as a potential target for an imaging tracer of atherosclerosis.…”

Soluble lectin-like oxidized low density lipoprotein receptor-1 in metabolic syndrome

“…The lectin-like oxidized low density lipoprotein receptor (LOX-1) is a receptor for oxidized low density lipoprotein (oxidized LDL) and has been implicated in vascular inflammation, and atherosclerotic plague 676 P. Puttaruk, et al formation and destabilization [8,9]. Binding of oxidized LDL to LOX-1 on vascular endothelial cells leads to the activation of nuclear factor-κb, resulting in endothelial cell dysfunction and increases in monocyte adhesion [10].…”

“…Binding of oxidized LDL to LOX-1 on vascular endothelial cells leads to the activation of nuclear factor-κb, resulting in endothelial cell dysfunction and increases in monocyte adhesion [10]. Proinflammatory and oxidative stimuli during atherogenesis, and advanced atherosclerotic plaques prominently upregulate LOX-1 expression [8,11,12]. LOX-1 is a type II membrane protein containing 4 domains including: a short N-terminal cytoplasmic domain, a transmembrane domain, a neck domain, and a lectin-like extracellular C-terminal domain [13,14].…”

Tissue Factor Detection for Selectively Discriminating Unstable Plaques in an Atherosclerotic Rabbit Model

“…In human pathologic lesions, the TF content of de novo lipid-rich plaques was higher than that of stenotic fibrous plaques (4), and such lipid-rich plaque tissue was 6 times more thrombogenic than fibrous plaques. In addition, our recent study also demonstrated that TF expression was closely related to plaque vulnerability, with high TF expression specifically in macrophage-rich atheromatous lesions among heterogeneous atherosclerotic lesions (5). Given these data, TF is a potential target for probes detecting atheromatous lesions at higher risk for rupture in vivo.…”